CADASIL causes progressive damage of the small blood vessels in the brain. This is caused by mutations in the NOTCH3 gene, which codes for the Notch3 protein. A characteristic feature of the disease is deposits of abnormal material called Granular Osmiophilic Material (GOM) in the blood vessel wall.
The CADASIL genetic mutations result in the build-up of part of the Notch3 protein near the GOM deposits in the blood vessel walls. These Notch3 protein deposits were initially thought to encourage the formation of GOM, although how this occurred was uncertain. Recent studies have shed light on a possible disease pathway in CADASIL.
Researchers in France examined these Notch3 protein segment aggregates, and found that there were two other proteins present as well. Two of these proteins, known as TIMP3 and Vitronectin, have roles in stabilising the extracellular matrix, a supporting tissue which forms the scaffold of blood vessels. These function by controlling enzymes which break down and increase the turnover of the scaffold.
The deposition of the Notch3 protein segment may be the beginning of a domino effect. Notch3 segments were found to bind to TIMP3, promoting its accumulation in the blood vessel walls. This in turn led to the further recruitment of other proteins including vitronectin. The deposition of TIMP3 and Vitronectin in the walls of small blood vessels leads to their increased activity, resulting in increased turnover of the vessel scaffolding, and thus the increased fragility of the blood vessel walls.
Subsequently, another group in Germany found that the Notch3 protein deposits also bind to and promote the accumulation of another protein (LTBP1), which has roles in maintaining a cellular signalling pathway. The disruption of this signalling pathway has been shown to cause organ scarring of other diseases.
These findings have identified early events in the CADASIL, significantly improving our current understanding of CADASIL, and possibly informing future work on the development of targeted therapy.
1. Monet-Leprêtre M, Haddad I, Baron-Menguy C, et al. (2013) Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: a new pathomechanism in CADASIL. Brain 136:1830–45. Click here for PubMed abstract
2. Kast J, Hanecker P, Beaufort N, et al. (2014) Sequestration of latent TGF-β binding protein 1 into CADASIL-related Notch3-ECD deposits. Acta Neuropathol Commun 2:96. Click here for PubMed abstract